Regulatory Th2 response induced following adoptive transfer of dendritic cells in prediabetic NOD mice

Abstract

We previously demonstrated that immunotherapy with dendritic cells (DC) prevented diabetes development in prediabetic NOD mice and that this effect was optimal when using a stimulatory DC population generated from bone marrow cells cultured with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and IL‐4. In this study, we have investigated the mechanism by which GM‐CSF‐ and IL‐4‐cultured DC prevent diabetes in prediabetic NOD mice. Histological analysis of pancreatic tissue from DC‐treated mice revealed a reduction in the severity of insulitis compared to controls. Analysisof the T cell response in DC‐treated mice suggested a general shift towards a Th2‐dominated response, as determined by cytokine production following either concanavalin A or anti‐TCR stimulation. Furthermore, sorted CD45RBlo CD25+ CD4+ T cells from the spleen of DC‐treated mice produced high amounts of Th2 cytokines following anti‐TCR stimulation, suggesting that these cells are responsible for the apparent Th2 shift. We conclude that DC therapy may have corrected the immunoregulatory defect in the NOD mouse, thus restoring a balance between pathogenic Th1 cells and protective Th2 cells.

IgG4 subclass glutamic acid decarboxylase antibodies (GADA) are associated with a reduced risk of developing type 1 diabetes as well as increased C-peptide levels in GADA positive gestational diabetes

“…In setting dominated by Th1/Th17 cells, the local cytokine profile will induce an isotype switch towards the human IgG 1 subclass [7,8], while Th2 cells will induce an isotype switch towards the human IgG 4 subclass [9]. Whether this actually may prevent type 1 diabetes or not will need to be further investigated in future studies, but promising results have been shown in NOD mice [10,11].…”

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

“…Several mechanisms of action have been suggested in the past [6,7,35] for the effect of DC and/or IL-4 in NOD mice. We opted for a different approach, using microarray analysis, to get a broader picture of the impact of DC/IL-4 treatment on gene expression in targeted tissues.…”

Impaired IL‐4 production by CD8+ T cells in NOD mice is related to a defect of c‐Maf binding to the IL‐4 promoter

“…After 3-5 days in culture, the cells were restimulated (5Â10 5 /ml) with anti-TCR and soluble anti-CD28 for 24 h. Supernatants were collected for determination of cytokine production by ELISA as reported [36]. The cells for RT-PCR of c-Maf, EMSA and ChIP were obtained from 5-day T cell differentiation cultures, in which cells were expanded on day 3 in the presence of respective cytokines and antibodies followed by restimulation with PMA and ionomycin for 5 h.…”